The FDA has accepted a supplemental new drug application (sNDA) for darolutamide (Nubeqa) in combination with androgen deprivation therapy (ADT) for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC). This decision is based on data from the phase 3 ARANOTE trial, which demonstrated a statistically significant improvement in radiographic progression-free survival (rPFS) for patients treated with darolutamide plus ADT compared to placebo plus ADT.
The ARANOTE trial (NCT04736199) was a global, randomized, double-blind, placebo-controlled study involving patients with mHSPC who had an ECOG performance status of 0 to 2. Patients were randomized in a 2:1 ratio to receive either darolutamide 600 mg twice daily plus ADT or placebo plus ADT. The primary endpoint was rPFS, assessed by central blinded review. Key secondary endpoints included overall survival (OS), time to subsequent anticancer therapy, time to metastatic castration-resistant prostate cancer (mCRPC), and safety.
ARANOTE Trial Results
Data from the ARANOTE trial, presented at the 2024 ESMO Congress, showed that the median rPFS was not reached (NR) in the darolutamide plus ADT arm compared to 25.0 months (95% CI, 19.0-NR) in the placebo plus ADT arm (HR, 0.54; 95% CI, 0.41-0.71; P < .0001). The 24-month rPFS rates were 70.3% and 52.1%, respectively, demonstrating a clinically meaningful benefit with the darolutamide regimen.
At the data cutoff of June 7, 2024, overall survival (OS) data were immature. The median OS was NR in both the darolutamide and placebo arms (HR, 0.81; 95% CI, 0.59-1.12). The median time to mCRPC was NR in the darolutamide arm versus 13.8 months in the placebo arm (HR, 0.40; 95% CI, 0.32-0.51).
Other secondary endpoints also favored the darolutamide arm. The median time to PSA progression was NR in the darolutamide arm versus 16.8 months in the placebo arm (HR, 0.31; 95% CI, 0.23-0.41). The time to subsequent systemic therapy was NR in both groups (HR, 0.40; 95% CI, 0.29-0.56), and the median time to pain progression was NR in the darolutamide group versus 29.9 months in the placebo group (HR, 0.72; 95% CI, 0.54-0.96).
Safety Profile
The safety profile of darolutamide plus ADT was consistent with previous studies. Any-grade treatment-emergent adverse events (TEAEs) occurred in 91.0% of patients in the darolutamide arm and 90.0% in the placebo arm. Grade 3 or 4 TEAEs were reported in 30.8% and 30.3% of patients, respectively. Serious TEAEs occurred in 23.6% of patients receiving darolutamide and 23.5% receiving placebo. TEAEs led to treatment discontinuation in 6.1% of patients in the darolutamide arm and 9.0% in the placebo arm.
Specific TEAEs associated with androgen receptor pathway inhibitors included fatigue (darolutamide arm, 5.6%; placebo arm, 8.1%), mental impairment disorder (1.6%; 0.5%), hypertension (9.4%; 9.5%), and cardiac arrhythmias (8.8%; 6.8%).
Implications for mHSPC Treatment
"Bayer is dedicated to addressing unmet needs in prostate cancer treatment for various stages of the disease," said Christine Roth, Executive Vice President at Bayer. "If approved, this would expand the indication for darolutamide in patients with mHSPC to include darolutamide both with and without chemotherapy, providing physicians and their patients with an additional darolutamide treatment option in this setting."
Darolutamide was previously approved by the FDA in combination with docetaxel for mHSPC in August 2022 and initially approved for non-metastatic castration-resistant prostate cancer (CRPC) in July 2019. The potential approval of darolutamide plus ADT would offer another valuable treatment option for patients with mHSPC.
